The present invention relates to a process for producing a 2,2-bis(fluoromethyl)-6-(perfluoroalkyl) -2H-1-benzopyran-4-carboxylic acid represented by the general formula [1], which is a 4-substituted benzopyran derivative useful as an intermediate for medicines and agricultural chemicals, 
wherein R1 is a perfluoroalkyl group that is represented by CnF2n+1 where n is an integer of 1-10 and that optionally has a branch in a carbon structure of the perfluoroalkyl group.
It is disclosed in WO/00/18754 and Bioorganic and Medicinal Chemistry 8 (2000), 1393-1405 that the above carboxylic acid can be synthesized by five (5) steps from a starting material of 2,2-bis(fluoromethyl)-6-(perfluoroalkyl)-2H-1-benzopyran-4-one (represented by the general formula [2]; hereinafter referred to xe2x80x9cbenzopyranone [2]xe2x80x9d for simplification) via 4-bromo- 2,2- bis(fluoromethyl)-6-(perfluoroalkyl)-2H- 1-benzopyran (represented by the general formula [11]), 
where R1 is defined as above. Hereinafter, various compounds may be referred to for simplification in a manner similar to that the benzopyranone represented by the general formula [2] is referred to as the benzopyranone [2]. As shown by the following scheme, the five steps are explained in more detail. At first, the benzopyranone [2] is reduced in the first step by sodium borohydride or the like. The resulting benzopyranol [12] is dehydrated in the second step by a dehydrating agent (e.g., xcfx81-toluenesulfonic acid). The resulting benzopyran derivative [13] is brominated in the third step by bromine. The resulting dibromobenzopyran [14] is reacted in the fourth step with a base. The resulting 4-bromobenzopyran [11] is reacted in the fifth step with carbon monoxide in the presence of a palladium complex compound and a base to obtain the benzopyran carboxylic acid [1], 
where R1 is defined as above.
It is further disclosed in WO/00/18754 that the 4-bromobenzopyran [1] is obtained by four steps from a 3,4-dihalogeno-1-perfluoroalkylbenzene [15], that it is obtained by four steps from an acetylene derivative [16], and that it is obtained by subjecting an acetylene derivative [17] to a thermal cyclization, 
where R1 is defined as above, and X and Y are independently halogen atoms.
Of the above-mentioned conventional processes, one using the benzopyranone [2] as a starting material has advantages over others in terms of reagents availability and selectivity of the reaction. However, even that process requires taking the above-mentioned five steps to obtain the benzopyran carboxylic acid [1], thus making it cumbersome. Therefore, there is a demand for a process for producing the benzopyran carboxylic acid with fewer steps.
The present invention further relates to a process for producing hydroxyacetophenones, which are useful as intermediates for medicines and agricultural chemicals, and particularly to 2-hydroxy-5-(perfluoroalkyl)acetophenones.
There are known the following two (2) processes for producing a 2-hydroxy-5-(perfluoroalkyl)acetophenone represented by the general formula [5], 
where R1 is defined as above.
DE 2653601 A1 discloses that 2-hydroxy-5-(trifluoromethyl)acetophenone was obtained by mixing together 4-(trifluoromethyl)phenol and hydrofluoric acid anhydride, then by adding acetyl chloride to the mixture, and then by heating the mixture at 100xc2x0 C. under a pressurized condition.
J. Chem. Soc., Chem. Commun. (1995) 19, 2009-10 discloses that 4-(trifluoromethyl)phenol and pinacolone were dissolved in benzene, followed by irradiation with light, thereby obtaining 2-hydroxy- 5-(trifluoromethyl)acetophenone with a yield of about 13%.
In general, benzene rings having a perfluoroalkyl group (e.g., trifluoromethyl group and pentafluoroethyl group) are low in reactivity in Friedel-Crafts type electrophilic substitution reactions. Thus, it is necessary to have a severe condition, for example, by heating at 100xc2x0 C. or higher or by light irradiation in the presence of a strong acid or strong base in order to directly introduce an acyl group onto 4-perfluoroalkylphenol by Friedel-Crafts reactions. Such severe condition, however, may gradually decompose the perfluoroalkyl group, thereby lowering selectivity of the target reaction. This may lower the yield of 2-hydroxy-5-(perfluoroalkyl)acetophenone or may makes it difficult to conduct purification by adverse effects of by-products.
Thus, there is a demand for processes for producing 2-hydroxy-5-(perfluoroalkyl)acetophenones in an industrial manner with a mild reaction condition.
It is therefore an object of the present invention to provide a process for efficiently producing a 2,2-bis(fluoromethyl) -6-(perfluoroalkyl)- 2H- 1 -benzopyran-4-carboxylic acid.
It is another object of the present invention to provide a process for producing 2-hydroxy-5-(perfluoroalkyl) acetophenones in an industrial manner under a mild reaction condition.
According to a first aspect of the present invention, there is provided a novel first process for producing a 2,2-bis(fluoromethyl)-6-(perfluoroalkyl)-2H- 1-benzopyran-4-carboxylic acid represented by the general formula [1]. The process comprises the steps of:
(a) reacting a 2,2-bis(fluoromethyl)-6-(perfluoroalkyl)-2H-1-benzopyran-4-one, represented by the general formula [2], with a perfluoroalkanesulfonic acid anhydride, represented by the general formula [3], in the presence of a base, thereby obtaining a perfluoroalkanesulfonic 2,2-bis(fluoromethyl)-6-(perfluoroalkyl)-2H-1-benzopyran-4-yl ester represented by the general formula [4]; and
(b) reacting the benzopyranyl ester with carbon monoxide in the presence of a palladium complex compound and a base, thereby obtaining the carboxylic acid, 
where R1 is a perfluoroalkyl group that is represented by CnF2n+1 where n is an integer of 1-10 and that optionally has a branch in a carbon structure of the perfluoroalkyl group;
each of R2 and R3 is independently a lower perfluoroalkyl group that is represented by CnF2n+1 where n is an integer of 1-10 and that optionally has a branch in a carbon structure of the lower perfluoroalkyl group; and
R4 is identical with the R2 or R3.
Hereinafter, the 2,2-bis(fluoromethyl)-6-(perfluoroalkyl)-2H- 1-benzopyran-4-one, represented by the general formula [2], may be referred to as the benzopyranone [2] for simplification. Various other compounds may also be referred to in a manner similar to this.
It is disclosed in Bioorganic and Medicinal Chemistry 8 (2000) 1393-1405 that the benzopyranone [2], which is the starting material of the step (a), can be produced by the step (e) reacting a 2-hydroxy-5-(perfluoroalkyl) acetophenone, represented by the general formula [5], with 1,3-difluoroacetone in the presence of a base, 
where R1 is defined as above. Thus, in case that this reaction is conducted prior to the step (a), the acetophenone [5] can be the starting material for producing the carboxylic acid [1].
According to a second aspect of the present invention, there is provided a novel second process for producing such acetophenone [5]. The second process comprises the steps of:
(c) reacting a 4-(perfluoroalkyl)alkoxybenzene, represented by the general formula [6], with acetic anhydride or an acyl halide in the presence of a Lewis acid, thereby obtaining a 2- alkoxy-5- (perfluoroalkyl)acetophenone represented by the general formula [7]; and
(d) dealkylating the 2-alkoxy-5-(perfluoroalkyl) acetophenone by a dealkylating agent, thereby obtaining the 2 -hydroxy-5 - (perfluoroalkyl) acetophe none, 
where R1 is defined as above; and R5 is a straight-chain or non-straight-chain alkyl group having a carbon atom number of 1-20. Thus, it is possible by the present invention to produce the carboxylic acid [1] from the alkoxybenzene [6] by sequentially conducting the steps of (c), (d), (e), (a) and (b).
Furthermore, it is possible by the present invention to produce the alkoxybenzene [6] by the step (f) reacting a 4-(perfluoroalkyl)phenol represented by the general formula [8] with an alkylation agent or reacting a 4-(perfluoroalkyl) halogenobenzene represented by the general formula [9] with a metal alcoholate. 
where R1 is defined as above and X is a fluorine, chlorine, bromine or iodine. Thus, it is possible by the present invention to produce the carboxylic acid [1] from the phenol [8] or the halogenobenzene [9] by sequentially conducting the steps of (f), (c), (d), (e), (a) and (b), as shown by the following scheme in which the numbers represent the above-mentioned general formulas and in which the letters of xe2x80x9caxe2x80x9d to xe2x80x9cfxe2x80x9d represent the above-mentioned steps. 
As stated above, it is possible by the first process to obtain the target product (i.e., the benzopyrancarboxylic acid [1]) from the benzopyranone [2] (starting material) by only the two steps of (a) and (b) without producing the 4-bromobenzopyran [11] as an intermediate.
In fact, the present inventors have found that it is possible to very smoothly obtain the sulfonic ester [4] by reacting the benzopyranone [2] with the perfluoroalkane-sulfonic acid anhydride [3] in the presence of a base (i.e., the step (a)) and that it is possible to easily obtain the target benzopyrancarboxylic acid [1] by reacting the sulfonic ester [4] (obtained by the step (a)) with carbon monoxide in the presence of a palladium complex compound and a base, as shown by the following reaction scheme. 
The first process according to the present invention will be described in detail in the following. As stated above, the substituent R1 is a perfluoroalkyl group that is represented by CnF2n+1 where n is an integer of 1-10 and that optionally has a branch in its carbon structure. In view of its availability, n is preferably 1, 2 or 3. In this case, R1 is trifluoromethyl group, pentafluoroethyl group, heptafluoro-n-propyl group, or heptafluoro-i-propyl group. Of these, trifluoromethyl group (where n=1) is particularly preferable in view of its availability and usefulness of the target product.
The step (a) may be conducted at a temperature of 0-100xc2x0 C., preferably 0-60xc2x0 C., more preferably 0-30xc2x0 C.
It is necessary to conduct the step (a) in the presence of a base. The type of this base is not particularly limited. It is preferable to select the base from pyridines (e.g., pyridine, monomethylpyridines, dimethylpyridines, monoethylpyridines, trimethylpyridines, 2,6-di-tert-butyl-4-methylpyridine, and 4-dimethylaminopyridine (DMAP)). Although the amount of the base is not particularly limited, it is preferably 1-10 moles, more preferably 1-4 moles, per mol of the benzopyranone [2]. If it is less than 1 mol, the reaction may not proceed sufficiently. If it is greater than 10 moles, it may cause an economical disadvantage.
Examples of the sulfonic acid anhydride [3] are trifluoromethanesulfonic acid anhydride and pentafluoroethanesulfonic acid anhydride. In the general formula [3], R2 and R3 may be different perfluoroalkyl groups.
However, sulfonic acid anhydrides [3] having such R2 and R3 are generally high in price. Therefore, it is preferable to use one in which R2 and R3 are the same perfluoroalkyl groups. It is particularly preferable to use trifluoromethanesulfonic acid anhydride due to its availability. The amount of the sulfonic acid anhydride [3] used in the reaction may be 1-15 moles, preferably 1-5 moles, more preferably 1-3 moles, per mol of the benzopyranone [2]. If it is less than 1 mol, the reaction may not proceed sufficiently. If it is greater than 15 moles, it may cause an economical disadvantage.
It is preferable to use a solvent in the step (a). This solvent is not particularly limited. Its preferable examples include methylene chloride, chloroform, carbon tetrachloride, and 1,2-dichloroethane. Although the time for completing the step (a) may be approximately in a range of 10-200 hrs, it may deviate from this range depending on the reaction conditions. Therefore, it is preferable to terminate the reaction after confirming that the raw materials have been consumed sufficiently by monitoring the progress of the reaction using a conventional analytical technique such as liquid chromatography or thin layer chromatography.
The purification operation after the step (a) is not particularly limited and can be conducted by normal techniques in the field of organic synthesis. For example, the reaction mixture can be washed with water, followed by extraction with a low-boiling-point organic solvent, column chromatography, recrystallization, and removal of the solvent by distillation, thereby obtaining the sulfonic ester [4].
The benzopyranone [2] used in the step (a) is not limited at all with respect to its synthesis. For example, it is particularly economically preferable to obtain the benzopyranone [2] by the above-mentioned step (e) reacting the acetophenone [5] with 1,3-difluoroacetone in the presence of a base, as shown by the following scheme. 
The step (e) can be conducted by mixing together the acetophenone [5], 1,3-difluoroacetone and a base, and then by stirring the mixture in the presence of a solvent at a temperature of preferably 0-60xc2x0 C., more preferably 20-40xc2x0 C., thereby synthesizing the benzopyranone [2]. For example, the base and the solvent are respectively pyrrolidine and methanol, but are not limited thereto. It is possible to achieve the reaction of the step (e) by mixing together 1 part by mole of the acetophenone [5], 1 part by mole of 1,3-difluoroacetone, and 1 part by mole of a base. The reaction is, however, not limited to these relative amounts. It is possible to improve conversion of the reaction by using the base and 1,3-difluoroacetone in slightly excessive amounts relative to that of the acetophenone [5]. For example, each of the former compounds may be in an amount of 1-5 moles, preferably 1-2 moles, per mol of the latter compound. The reaction mixture obtained by the step (e) may be subjected to a normal purification procedure of organic syntheses, thereby separating the target benzopyranone [2]. The step (e) and the subsequent purification procedure may be conducted in accordance with the disclosure of Bioorganic and Medicinal Chemistry 8 (2000), 1393-1405 and may be modified by a person skilled in the art.
The step (b) will be described in detail in the following. As stated above, the step (b) is conducted by reacting the sulfonic ester [4] with carbon monoxide in the presence of a palladium complex compound and a base, thereby obtaining the carboxylic acid [1]. The palladium complex compound is not particularly limited. Its examples include bis(dibenzylideneacetone)palladium (Pd(dba)2), tris(dibenzylidene) (chloroform) dipalladium (Pd2(dba)3(CHCl3)), tetraquis(triphenylphosphine)palladium (Pd(PPh3)4), palladium acetate Pd(OCOMe)2, PdCl2, PdBr2, PdCl2(PPh3)2, Pd(OCOMe)2(PPh3)2, PdBr2(PPh3)2, PdCl2(PMe3)2, PdCl2[P(Ph)2CH2CH2P(Ph)2], PdCl2[P(Ph)2CH2CH2CH2P(Ph)2], PdCl2[P(Ph)2CH2CH2CH2CH2P(Ph)2], and Pd2Br4(PPh3)2, where Me and Ph represent methyl group and phenyl group, respectively. The amount of the palladium complex compound used in the reaction may be 0.00001-0.5 moles, preferably 0.00005-0.1 moles, more preferably 0.0001-0.1 moles, per mol of the sulfonic ester [4]. If it is less than 0.00001 moles, the reaction rate may become too slow, making it disadvantageous to an industrial production. Although an amount greater than 0.5 moles does not cause particular problems in conducting the reaction, it may become uneconomical.
It is optional to add a phosphine in the step (b), since it may stabilize the palladium complex compound in some cases to make the reaction proceed preferably. The phosphine may be selected from common phosphines, such as triphenylphosphine, tri-o -tolylphosphine, triethylphosphine, tri-n-butylphosphine, 1,1xe2x80x2-bis(diphenylphosphino)ferrocene (dppf), 1,4-bis(diphenylphosphino)butane, 1, 3-bis(diphenylphosphino)propane, and 1,2-bis(diphenylphosphino)ethane. The phosphine used in the step (b) may be in an amount of 10 moles or less, preferably 5 moles or less, more preferably 3 moles or less, per mol of the palladium complex compound. If it is greater than 10 moles, the reaction rate may become too slow. Furthermore, it may become uneconomical. The step (b) can proceed without adding a phosphine. In particular, in case that the after-explained neutral inorganic salt is coexistent with the other reactants, it is possible to obtain a sufficient reaction rate with no addition of phosphine.
A base is essential for the step (b). Its nonlimitative examples are inorganic bases such as potassium acetate, sodium acetate, sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate; and organic bases such as triethylamine, tripropylamine, tri-n-octylamine, triallylamine, pyridine, and N,N-dimethylaniline. The base may be in an amount of 1-10 moles, preferably 1-5 moles, more preferably 1-3 moles, per mol of the sulfonic ester [4]. If it is less than 1 mole, the reaction may not proceed sufficiently, causing low yield. An amount greater than 10 moles does not increase the yield further and makes the unreacted base remain in the system. This is economically disadvantageous.
The step (b) can be conducted in a solvent or without using any reaction solvent. The solvent may be selected from pentane, hexane, benzene, toluene, xylene, diethyl ether, dioxane, tetrahydrofurane, acetone, methyl isobutyl ketone, acetonitrile, pyridine, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, and water. In case that the base is in the form of liquid, it serves as a solvent, too. With this, it is possible to obtain an effect similar to the case of adding a solvent.
It is particularly preferable to add a neutral inorganic salt in the step (b), since it enhances the reaction rate and allows the reaction to proceed at a lower temperature with an improved yield. Its nonlimitative examples are potassium fluoride, potassium chloride, potassium bromide, potassium iodide, lithium fluoride, lithium chloride, lithium bromide, and lithium iodide. The neutral inorganic salt may be in an amount of 0.01-10 moles, preferably 0.1-5 moles, more preferably 0.5-2 moles, per mol of the sulfonic ester [4]. If it is less than 0.01 moles, the advantageous effect caused by adding the neutral inorganic salt may be insufficient. An amount greater than 10 moles may not further improve the yield and may become economically disadvantageous.
The reaction of the step (b) can be conducted by charging a reactor with the above-mentioned reagents, then by sealingly closing the reactor, then by introducing carbon monoxide into the reactor, and then by stirring the mixture under normal pressure (e.g., atmospheric pressure) or a pressurized condition. It is optional to make another gas (preferably inert gas such as nitrogen, helium and argon) other than carbon monoxide coexistent with the other reagents. Each of the air and oxygen is not preferable as the another gas, since it may lower the palladium catalytic activity. Normally, it is not necessary to use the another gas. The partial pressure (in terms of absolute pressure) of carbon monoxide is preferably 0.01-10 MPa, more preferably 0.05-1.5 MPa. If it is lower than 0.01 MPa, the reaction may not proceed sufficiently, thereby lowering yield. Even if it is higher than 10 MPa, the yield of the target product may not improve further. Furthermore, it may require the reactor to have an improved strength. As the reaction proceeds in the step (b), carbon monoxide is consumed either under normal pressure or under pressurized condition. Therefore, it is preferable to introduce carbon monoxide intermittently or continuously into the system in order to maintain the carbon monoxide partial pressure at a constant level. The reaction temperature of the step (b) may be in a range of 0-200xc2x0 C., preferably 0-150xc2x0 C., more preferably 0-120xc2x0 C. The optimum reaction temperature may be changed depending on the types and the amounts of the reagents (e.g., palladium complex compound, neutral inorganic salt, and base).
After completing the step (b), the reaction mixture may be subjected to a normal purification procedure. For example, it is possible to add a large excess of water to the reaction mixture, followed by sufficient stirring, extraction with an organic solvent, and removal of the solvent by distillation, thereby obtaining the benzopyrancarboxylic acid [1].
The second process will be described in detail in the following. As stated above, it is possible by the second process to easily synthesize the target product (i.e., the acetophenone [5]) from the alkoxybenzene [6] (starting material). In fact, the present inventors have unexpectedly found that the alkoxybenzene [6] is remarkably higher than 4-(perfluoroalkyl)phenol [8] with respect to (a) chemical stability and (b) reactivity in Friedel-Crafts type electrophilic substitution reactions and that an acylation of the alkoxybenzene [6] proceeds smoothly under a mild condition of 50xc2x0 C. or lower by reacting the alkoxybenzene [6] with acetic anhydride or an acyl halide in the presence of a Lewis acid, thereby easily synthesizing 2-alkoxy-5-(perfluoroalkyl) acetophenone [7].
The alkoxybenzene [6] can easily be produced by reacting the 4-(perfluoroalkyl)phenol [8] with an alkylation agent or by reacting a 4-(perfluoroalkyl)halogenobenzene [9] with a metal alcoholate.
The reaction scheme from the 4-(perfluoroalkyl)phenol [8] or 4-(perfluoroalkyl)halogenobenzene [9] to the acetophenone [5] can be shown as follows. 
Similar to the first process, the substituent R1 of the general formulas [5] to [9] is a perfluoroalkyl group that is represented by CnF2n+1 where n is an integer of 1-10 and that optionally has a branch in its carbon structure. In view of its availability, n is preferably 1, 2 or 3. In this case, R1 is trifluoromethyl group (CF3), pentafluoroethyl group (C2F5), heptafluoro-n-propyl group (CF3CF2CF2), or heptafluoro-i-propyl group (CF3CFCF3). Of these, trifluoromethyl group (where n=1) is particularly preferable in view of its availability and usefulness of the target product, 2-hydroxy-5- (trifluoromethyl) acetophenone [5].
R5 of the general formulas [6] and [7] is a straight-chain or non-straight-chain alkyl group having a carbon atom number of 1-20. In view of its availability, R5 is preferably methyl group, ethyl group, n-propyl group or i-propyl group, particularly preferably methyl group.
The intermediate of the second process, 2-methoxy-5-(trifluoromethyl)acetophenone represented by the following formula [10], where R1 is CF3 and R5 is methyl group, is a novel compound. 
As stated above, the step (c) can be conducted by reacting the alkoxybenzene [6] with acetic anhydride or an acyl halide in the presence of a Lewis acid, thereby synthesizing the acetophenone [7]. The step (c) will be described in detail in the following.
Although the order of adding the reagents is not particularly limited in the step (c), it is preferable that the alkoxybenzene [6] is mixed with acetic anhydride or an acyl halide, and then the resulting mixture is added intermittently or continuously in a dropwise manner to a reaction vessel containing a Lewis acid (e.g., trifluoromethanesulfonic acid), since this procedure makes it easy to control the reaction temperature.
Although the reagents of the step (c) are not particularly limited in their relative amounts, it is preferable that the acetic anhydride or acyl halide and the Lewis acid are in equimolar amounts or slightly greater relative to that of the alkoxybenzene [6]. For example, it is preferable that the acetic anhydride or acyl halide is in 1.0-3.0 moles and the Lewis acid is in 1.0-10.0 moles relative to 1.0 mol of the alkoxybenzene [6]. If the acetic anhydride or acyl halide and the Lewis acid are in amounts less than their preferable lower limit (i.e., 1.0 mole), yield of the acetophenone [7] may become too low. Even if they are in amounts greater than their preferable upper limits (i.e., 3.0 moles and 10.0 moles), the reaction proceeds. This, however, may become economically disadvantageous.
The Lewis acid used in the step (c) is not limited to particular types. Its preferable examples include trifluoromethanesulfonic acid, hydrofluoric acid anhydride, fuming sulfuric acid, and sulfuric acid. Of these, trifluoromethanesulfonic acid is particularly preferable, since it is in the form of liquid at normal temperature (e.g., room temperature) and thereby easy for handling and since it is high in activity as a Lewis acid. In the step (c), it is not preferable to use aluminum chloride anhydride, which is often used as a catalyst in Friedel-Crafts type electrophilic substitution reactions, since it tends to replace a fluorine atom(s) of a perfluoroalkyl group (e.g., trifluoromethyl group and pentafluoroethyl group) directly bonded to the benzene ring with a chlorine atom(s).
In the step (c), acetic anhydride or an acyl halide (e.g., acetyl fluoride, acetyl chloride, acetyl bromide and acetyl iodide) is used as an acylation agent. Of these, acetic anhydride is particularly preferable, since it is particularly high in reactivity. It is optional to use other aclyation agents and to use a plurality of acylation agents at the same time.
The step (c) is usually conducted in a solvent. However, in case that a Lewis acid (e.g., trifluoromethanesulfonic acid) in the form of liquid is used in the reaction, the Lewis acid serves as a reaction solvent, too. Therefore, there is no need for adding another reaction solvent. The another reaction solvent may be selected from carbon disulfide, dichloromethane, carbon tetrachloride, and 1,2-dichloroethane.
The reaction temperature of the step (c) is not particularly limited. It is preferably 0-50xc2x0 C., more preferably 0-30xc2x0 C., from the viewpoint of suppressing the decomposition of the perfluoroalkyl group (R1). Although the time for completing the step (c) may be approximately in a range of 1-12 hrs, it may vary depending on the reaction conditions. Therefore, it is preferable to terminate the reaction after confirming that the alkoxybenzene [6] has been consumed sufficiently by monitoring the progress of the reaction using a conventional analytical technique such as gas chromatography or liquid chromatography.
The purification process after the step (c) is not particularly limited. For example, it is possible to wash the reaction liquid with water to remove salts, aqueous unreacted components and the like, followed by extraction with a nonaqueous organic solvent and then removal of the solvent by distillation, thereby obtaining the alkoxyacetophenone [7].
The step (f) for producing the alkoxybenzene [6] will be described in detail in the following. It is possible to easily produce the alkoxybenzene [6] by the process (a) in which the 4-(perfluoroalkyl)phenol [8] is reacted with an alkylation agent or by the process (b) in which the 4-(perfluoroalkyl) halogenobenzene [9] is reacted with a metal alcoholate (e.g., sodium methoxide).
The process (a) of the step (f) can be conducted by any one of conventional techniques for alkylating hydroxyl group. As a first technique, 4-(perfluoroalkyl)phenol [8] can be reacted with an alkyl sulfate (e.g., dimethyl sulfate and diethyl sulfate), alkyl carbonate (e.g., dimethyl carbonate and diethyl carbonate) or alkyl halide (e.g., methyl chloride) in the presence of a base. As a second technique, it can be reacted with a diazoalkane compound (e.g., diazomethane). As a third technique, it can be reacted with an olefinic compound in the presence of an acid catalyst. Of these techniques, the first technique is particularly preferable, since the raw materials are easily accessible and since the reaction proceed mildly.
It is preferable to conduct the process (a) in a solvent. Although this solvent is not limited to particular types, it is preferable to use a polar solvent to make the reaction proceed mildly. Exemplary polar solvents include acetone, acetonitrile, methanol, ethanol, N,N-dimethylformamide, and nitromethane. Of these, acetone is particularly preferable, since it is chemically stable and thereby easy for handling.
In the first technique of the process (a), it is necessary to add a base in an amount of 1.0-1.5 moles (in the case of a monovalent base such as sodium hydroxide) or 0.5-1.0 mole ( in the case of a bivalent base such as potassium carbonate) per mol of the 4-(perfluoroalkyl)phenol [8]. The base is not limited to particular types, and it can be selected from common bases such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, and calcium hydroxide. It is possible to conduct the reaction by adding a base to the 4-(perfluoroalkyl)phenol [8], then by stirring the mixture sufficiently, and then by adding an alkylation agent, followed by stirring. The alkylation agent is in an amount of preferably 0.5-3.0 moles, more preferably 0.5-1.5 moles, per mol of the 4-(perfluoroalkyl)phenol [8], in the case of an alkylation agent having two alkyl groups in the molecule. Although the reaction temperature is not particularly limited, it is preferably 0-100xc2x0 C., more preferably 10-60xc2x0 C., throughout the process (a). In order to properly control the reaction temperature, it is preferable to mix the reagents intermittently or continuously.
In the process (a), the period of time required from completion of mixing all the reagents until completion of the reaction may be approximately 2-6 hrs. However, it may vary depending on the reaction conditions. Therefore, it is preferable to conduct the reaction, while monitoring its progress by a common analytical technique such as gas chromatography.
The process (b) of the step (f) can be conducted by adding in a polar solvent (e.g., methanol and ethanol) a metal alcoholate (e.g., sodium methoxide, lithium methoxide, sodium ethoxide, and lithium ethoxide) in an amount preferably 1-10 parts by mole, more preferably 1-5 parts by mole, to 1 part by mole of the halogenobenzene [9], followed by heating and stirring. The reaction temperature of the process (b) is preferably 80-200xc2x0 C., more preferably 120-180xc2x0 C. If it is higher than boiling point of the solvent, it is necessary to conduct the reaction in a pressure-proof reaction vessel in a tightly sealed condition. Although the time required for the reaction may be about 3-10 hrs, it may vary depending on the reaction conditions. Therefore, it is preferable to conduct the reaction, while monitoring the progress of the reaction using gas chromatography or liquid chromatography.
In each of the processes (a) and (b), the reaction mixture obtained by completing the reaction may be subjected to a normal purification procedure of organic syntheses, thereby separating the alkoxybenzene [6]. For example, the reaction mixture can be distilled by an evaporator to remove the solvent, followed by washing sufficiently with water, then extraction with a nonaqueous organic solvent, then removal of the solvent by distillation, and then distillation of the residue, thereby obtaining the alkoxybenzene [6].
The step (d) of dealkylating the acetophenone [7] by a dealkylating agent to obtain the acetophenone [5] will be described in detail in the following.
The reaction of the step (d) can be conducted by mixing together the acetophenone [7] and a dealkylating agent and then by stirring the mixture. The dealkylating agent is not particularly limited with respect to its type and operational procedure, and it may be selected from generally known dealkylating agents such as concentrated sulfuric acid, concentrated hydrochloric acid, concentrated nitric acid, hydrobromic acid (HBr) aqueous solution, hydroiodic acid (HI) aqueous solution, boron tribromide (BBr3), and boron trichloride (BCl3), and sodium hydroxide.
In some cases, the dealkylation of the step (d) may not proceed sufficiently even if the acetophenone [7] is reacted with a dealkylating agent. In contrast, a drastic heating for accelerating the dealkylation may generate undesirable side reactions (e.g., decomposition of perfluoroalkyl group). Thus, the present inventors eagerly examined the solution of such problems of the dealkylation. As a result, the present inventors unexpectedly found that the above-mentioned problems can be solved by.any one of the following three methods.
The first method is that the alkoxyacetophenone [7] is reacted with boron tribromide (BBr3). It is preferable to conduct this reaction in a solvent. Although this solvent is not limited to particular types, methylene chloride is particularly preferable since it allows the reaction to proceed smoothly. It is preferable to conduct the reaction at xe2x88x9250xc2x0 C. or lower under nitrogen gas flow, more preferably at xe2x88x9278xc2x0 C. or lower under nitrogen gas flow. For the purpose of keeping the reaction conditions constant, it is preferable to conduct the first method by separately dissolving the alkoxyacetophenone [7] and boron tribromide in methylene chloride to prepare two solutions, then by gradually adding one of these solutions in a dropwise manner to the other solution while stirring the other solution, and then by continuing stirring under the same condition. Although the stirring time may be about 1-5 hrs, it may deviate therefrom depending on the reaction conditions. In the first method, boron tribromide is in an amount preferably 0.33-2.0 moles relative to 1 mol of the alkoxyacetophenone [7].
The second method of the step (d) is that the alkoxyacetophenone [7] is reacted with sodium iodide and trimethylsilylchloride in a solvent. Although this solvent is not limited to particular types, it is preferable to use acetonitrile since it allows the reaction to proceed mildly. It is preferable to conduct the second method by dissolving the alkoxyacetophenone [7] and sodium iodide in a solvent, then by adding trimethylsilylchloride in a dropwise manner to the mixture, and then continuing stirring of the mixture. Although the reagents of the second method are not particularly limited in their relative amounts, it is preferable that each of sodium iodide and trimethylsilylchloride is in a range of 1.0-3.0 moles per mol of the alkoxyacetophenone [7]. The reaction temperature is not particularly limited. The temperature, at which the reagents are mixed together, is preferably 10-40xc2x0 C. The temperature for the subsequent stirring is preferably the reflux temperature of acetonitrile if acetonitrile is used as the solvent. The period of time required for such refluxing (heating) may be about 5-70 hrs, but it may deviate therefrom depending on the reaction conditions.
The third method of the step (d) is conducted by dissolving a strong base, such as a metal hydride (e.g., sodium hydride) or a metal alkoxide (e.g., sodium methoxide), in a solvent to prepare a first solution, then by adding a thiol (e.g., ethanethiol and 1-octanethiol) to the first solution to prepare a second solution (a solution of a metal salt of thiol), then by adding the alkoxyacetophenone [7] to the second solution, and then by continuing stirring of the resulting solution. Although the solvent of the third method is not limited to particular types, it is particularly preferable to use N,N-dimethylformamide since it allows the reaction to proceed mildly. The reaction temperature is not particularly limited. The temperature, at which the second solution is prepared, is preferably 0-30xc2x0 C. The temperature, at which the alkoxyacetophenone [7] is added to the second solution and then the stirring is conducted, is preferably 0-100xc2x0 C. Although the period of time for the stirring may be 15 minutes to 2 hrs, it may deviate therefrom depending on the reaction conditions. Although the reagents of the third method are not particularly limited in their relative amounts, it is preferable that each of the strong base and the thiol is in an equimolar amount or greater relative to that of the alkoxyacetophenone [7]. For example, each of them is preferably in 1.0-1.1 moles relative to 1.0 mole of the alkoxyacetophenone [7] in terms of reactivity and economy.
In each of the first to third methods of the step (d), it is preferable to conduct the reaction, while monitoring the progress of the reaction by using a normal analytical technique such as gas chromatography and liquid chromatography. It is possible to terminate the reaction after confirming that the alkoxyacetophenone [7] has sufficiently been consumed.
The reaction mixture obtained by the step (d) may be subjected to a normal post-treatment. For example, the reaction mixture is sufficiently washed with water, followed by extraction with a nonaqueous organic solvent and then removal of this solvent by distillation, thereby obtaining the target product, the hydroxyacetophenone [5].
The following nonlimitative Examples are illustrative of the present invention.